It is well known that compounds capable of releasing nitrogen oxide (NO) into the organism exhibit in many cases some type of activity of the vascular system, for example vasodilating activity or inhibition of the aggregation of the platelets, which make them potentially useful for the treatment of different disorders related to dysfunctions of the circulatory system.
Further, it is described too that specific derivatives which contain an S-nitrosothiol group have, from a medical point of view, advantageous characteristics due to the fact that they are capable of releasing NO in the organism.
Radomski et al., Br. J. Pharmacol. (1992) 107, 745-749, describes that an S-nitrosoglutathione (GSNO) compound is capable of inhibiting the activity of the platelets.
Golino et al, Circulation Research, 71, No 6 (1992), describes that S-nitrosocysteine is capable of inhibiting the activity of the platelets, due to an anti-thrombosis effect.
Smith et al., Met. Find. Exp. Clime. Pharmacy. (1994), 16, 5, describes that the GSNO produces a strong relaxing effect of the arterioles.
WO95/12394 describes the use of S-nitroso adducts of peptides, among others the S-nitroso-N-acetylpenicillamine (SNAP), as protecting agents against vascular inflammation of traumatic origin.
WO95/07691 describes the use of different S-nitrosothiols, in particular the GSNO, in the treatment and prevention of the action of the platelets and the formation of thrombosis on damaged vascular surface.
WO93/09806 describes S-nitrosated proteins or amino acid residues, capable of releasing NO, which have a relaxing effect on the musculature and an inhibitory effect on platelet aggregation.
The S-nitrosothiol group is an unstable functional group and therefore the administration of active ingredients comprising the same possess many problems. The in vivo decomposition of the S-nitrosothiol functionality reduces the efficacy of some medicaments which show excellent in vitro activity. A further problem derived from the low stability of S-nitroso compounds is their short shelf stability.
EP-B1-1157987, in the name of the applicant, describes S-nitrosothiols derivatives of penicillamine or glutathione, which both have a potent vasodilating effect and a high inhibitory effect on the aggregation of the platelets of the formula
wherein A and B are phenyl groups or together form the residue —CH2-Q-CH2—constituting a ring of six units in which Q represents an atom of oxygen, of sulfur, or a group N—R3, in which R3 is hydrogen or an alkyl group C1-C4; R1 is an acyl residue, which may be an aliphatic acyl group C1-C5 or a residue of glutamic acid bound via its non amino acid carboxyl; R2 is a hydroxyl group or a glycine residue bound via a peptide bond. Although they show high efficacy, their usefulness is reduced due to the poor stability of the S-nitrosothiol functionality.
EP-B1-412699 describes S-nitrosothiols which correspond to following general formula:
and its use as therapeutic agents against cardiovascular diseases, in particular as anti-hypertension (increased blood pressure) and as agents for the treatment of angina pectoris. According to EP-B1-412699 the S-nitrosothiol functional group may be stabilized by bulky R1 and R2 groups.
Thus, there is a need for providing stable S-nitrosothiol derivatives.